Study of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy

• ClinicalTrials.gov Identifier: NCT01646021
• Recruitment Status: Completed
• First Posted: July 20, 2012
• Results First Posted: March 1, 2017
• Last Update Posted: January 19, 2018
• Sponsor: Janssen Research & Development, LLC
• Collaborator: Pharmacyclics LLC.
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: July 18, 2012
• First Posted Date: July 20, 2012
• Results First Submitted Date: June 2, 2016
• Results First Posted Date: March 1, 2017
• Last Update Posted Date: January 19, 2018
• Actual Study Start Date: December 10, 2012
• Actual Primary Completion Date: June 5, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 15, 2017)

Progression Free Survival (PFS) [ Time Frame: Time from the date of randomization until the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever occurred first (approximately 48 months) ]

PFS is defined as the duration in months from the date of randomization to the date of progression disease (PD) or relapse from complete response (CR) or death whichever was reported first and was assessed based on the investigator assessment. Revised Response Criteria for Malignant Lymphoma categorizes the response of the treatment of a patient's tumour to CR (the disappearance of all evidence of disease), Relapsed Disease or PD (Any new lesion or increase by greater than or equal to [>=] 50 percent [%] of previously involved sites from nadir).

• Original Primary Outcome Measures (submitted: July 18, 2012): Progression free survival [ Time Frame: clinical cutoff (defined by 178 patients with progression free survival events; up to 3 years after the last patient is randomized) ]

Current Secondary Outcome Measures (submitted: December 15, 2017)

• Overall Response Rate (ORR) [ Time Frame: Approximately up to 48 months ]
  ORR is defined as the percentage of participants who achieved either CR or PR as best overall response based on the investigator assessment. CR is Disappearance of all target lesions while PR is greater than or equal to 30 % decrease in the sum of the longest diameter of target lesions and Overall Response (OR) is sum of CR and PR.
• Overall Survival (OS) [ Time Frame: Approximately up to 48 months ]
  Overall survival (OS) was defined as the interval between the date of randomization and the date of death from any cause.
• Duration of Response [ Time Frame: Approximately up to 48 months ]
  Duration of response (CR or PR), defined as the duration in days from the date of initial response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death. The analysis was based on the investigator assessment.
• Time-to-Next Treatment [ Time Frame: Approximately up to 48 months ]
  Time to next treatment was measured from the date of randomization to the start date of any anti-neoplastic treatment subsequent to study treatment.
• Progression-Free Survival 2 [ Time Frame: Approximately up to 48 months ]
  Progression-free survival 2 defined as the time interval between the date of randomization and date of event, defined as progressive disease as assessed by investigator that started after the next line of subsequent anti-neoplastic therapy (including cross-over to ibrutinib), death from any cause, or the start of the second subsequent anti-neoplastic therapy if no progressive disease was recorded after the first subsequent anti-neoplastic therapy.
• Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym) [ Time Frame: Approximately up to 48 months ]
  Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life.
• Number of Participants Affected With Treatment-emergent Adverse Events [ Time Frame: Time from first dose of study drug until the last dose date + 30 days or the start of a subsequent anti-neoplastic therapy, whichever occur earlier (Approximately up to 4 years) ]
  An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Original Secondary Outcome Measures (submitted: July 18, 2012)

• Overall response rate [ Time Frame: up to 3 years after the last patient is randomized ]
• Overall survival [ Time Frame: up to 3 years after the last patient is randomized ]
• 1-year survival rate [ Time Frame: Month 12 ]
• Duration of response [ Time Frame: up to 3 years after the last patient is randomized ]
• Time-to-next treatment [ Time Frame: up to 3 years after the last patient is randomized ]
• Number of participants with adverse events [ Time Frame: up to 30 days after the last dose of study medication ]
• Mean plasma concentrations of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ]
• Maximum observed plasma concentration of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ]
• Minimum observed plasma concentration of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ]
• Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib [ Time Frame: Cycles 1-3: predose on Day 1; postdose at 1, 2, and 4 hours ]
• Mean change from baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale score [ Time Frame: up to 3 years after the last patient is randomized ]
• Mean change from baseline in EuroQol (EQ-5D-5L) index score [ Time Frame: up to 3 years after the last patient is randomized ]
• Mean change from baseline in medical resource utilization [ Time Frame: up to 30 days from last dose of study medication ]
• Mean change from baseline in biomarkers that alter B-cell receptor (BCR) signaling or activate alternative signaling pathways [ Time Frame: up to 30 days from last dose of study medication ]
• Mean change from baseline in identified resistance biomarkers from bone marrow [ Time Frame: up to 30 days from last dose of study medication ]

Current Other Pre-specified Outcome Measures (submitted: December 15, 2017)

• Time to Response [ Time Frame: Approximately up to 2.8 years ]
  Time to response for participants with CR/PR, defined as the interval between the date of randomization and date of initial documentation of response.
• Extent of Exposure of Time [ Time Frame: Approximately up to 46.8 months ]
  Extent of exposure is defined as the duration of the treatment administered during the study. Duration of exposure is calculated as the number of months between the start and end of treatment.
• One Year Survival Rate [ Time Frame: Month 12 ]
  One -year survival rate, defined as the proportion of participants who were alive 1 year after randomization.
• Area Under the Plasma Concentration of Ibrutinib During Steady State (AUC-ss) [ Time Frame: Cycle 1 and 2 (Day 1): Predose, 1, 2, 4 hr. postdose; Cycle 3 (day 1): Predose (Each cycle is of 21 days) ]
  The AUC-ss is the area under the plasma concentration time curve observed during steady state.
• Number of Participants With Biomarkers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib [ Time Frame: Approximately up to 28.2 months ]
  Biomarker evaluations to identify markers altering BCR signaling or activate alternative signaling pathways and explore their association with response or resistance to ibrutinib. Next-generation sequencing at baseline identifies possible primary resistance mutations and those found only at progression are acquired mutations on therapy.
• Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI) [ Time Frame: Approximately up to 28.2 months ]
  Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
• Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) [ Time Frame: Approximately up to 28.2 months ]
  Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
• Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) [ Time Frame: Approximately up to 28.2 months ]
  Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.
• The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment [ Time Frame: Baseline, Cycle 2, 3, 4, 5, 6, 7, 8, 11, 14, 17, 20, 28, 36 and End of treatment (approximately up to 23 months) ]
  The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 5 levels (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and possible total score range -0.594 to 1; higher score indicates a better health state.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
• Official Title: A Randomized, Controlled, Open-Label, Multicenter Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, Versus Temsirolimus in Subjects With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy
• Brief Summary: The purpose of this study is to evaluate the efficacy and safety of ibrutinib versus temsirolimus in patients with relapsed or refractory mantle cell lymphoma who received at least 1 prior chemotherapy regimen.
• Detailed Description: This is a randomized (individuals assigned to study treatment by chance), open-label (identity of assigned study drug will be known), study to evaluate the efficacy and safety of ibrutinib when compared with temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 1 prior rituximab-containing chemotherapy regimen. Approximately 280 eligible patients will be randomly assigned in a 1:1 ratio and stratified (grouped) by the number of prior lines of therapy (1 or 2 versus >=3) and simplified MCL International Prognostic Index criteria to receive either ibrutinib by mouth (Treatment Arm A) or temsirolimus intravenous infusion (Treatment Arm B). The study will consist of screening, treatment, and posttreatment phases. Data will be collected on disease response to the treatment, progression-free survival, overall survival, subsequent anti-MCL therapies, patient reported outcomes, and medical resource utilization. Tumor samples, blood collected at multiple time points, and a bone marrow aspirate will be evaluated to identify markers predictive of response or resistance to ibrutinib. Serial pharmacokinetic (study of what the body does to a drug) samples will be collected as detailed in the protocol. Safety will be monitored throughout the study. Disease evaluations will be performed every 9 weeks for up to 15 months from the start of study drug, and every 24 weeks thereafter, until disease progression, death, or the clinical cutoff, whichever comes first. Patients who receive treatment with temsirolimus and have disease progression (confirmed by an Independent Review Committee) may be eligible to crossover and receive treatment with ibrutinib 560 mg orally, daily, on a 21-day cycle until disease progression, unacceptable toxicity, or study end. Data will be analyzed up to 3 years after the last patient is enrolled for the final follow-up.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Mantle Cell Lymphoma

Intervention

• Drug: Ibrutinib
  560 mg once daily continuous (without interruption) by mouth for 21-day cycles
• Drug: Temsirolimus
  175 mg once daily intravenous infusion on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle

Study Arms

• Experimental: Ibrutinib
  Intervention: Drug: Ibrutinib
• Experimental: Temsirolimus
  Intervention: Drug: Temsirolimus

Publications *

• Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017 Oct;102(10):1796-1805. doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.
• Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016 Feb 20;387(10020):770-8. doi: 10.1016/S0140-6736(15)00667-4. Epub 2015 Dec 7. Erratum In: Lancet. 2016 Feb 20;387(10020):750.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 18, 2012): 280
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 15, 2016
• Actual Primary Completion Date: June 5, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Confirmed diagnosis of mantle cell lymphoma (MCL)
• Received at least 1 prior rituximab-containing chemotherapy regimen (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a > 6 month treatment-free interval)
• Documented relapse or disease progression following the last anti-MCL treatment
• At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
• Eastern Cooperative Oncology Group performance status grade 0 or 1
• Protocol-defined hematology and biochemistry laboratory values

Exclusion Criteria:

• Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational agents within 3 weeks, or major surgery within 4 weeks of randomization
• Prior treatment with temsirolimus, other mTOR inhibitors, ibrutinib, or other Bruton's tyrosine kinase (BTK) inhibitors
• Known central nervous system lymphoma
• Received an allogeneic or autologous hematopoietic stem cell transplant <=6 months from the date of randomization and on immunosuppressive therapy or have evidence of active graft versus host disease
• Diagnosed or treated for malignancy other than MCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before randomization, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated cervical carcinoma in situ without evidence of disease
• History of stroke or intracranial hemorrhage within 6 months prior to randomization
• Requires anticoagulation with warfarin or equivalent vitamin K antagonist
• Requires treatment with strong CYP3A inhibitor
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
• Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous antibiotics
• Woman who is pregnant or breast-feeding
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Brazil, Canada, Chile, Colombia, Czechia, France, Germany, Hungary, Ireland, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Russian Federation, Spain, Sweden, Taiwan, Ukraine, United Kingdom
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01646021
• Other Study ID Numbers: CR100848; PCI-32765MCL3001 ( Other Identifier: Janssen Research & Development, LLC ); 2012-000601-74 ( EudraCT Number ); U1111-1135-6930 ( Other Identifier: Universal Trial Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Pharmacyclics LLC.

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: December 2017